2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]1H-indole-5-carbonitrile as a free base and pharmaceutically acceptable salts thereof are known and useful because they possess pharmacological activity by showing inhibiting effect on GSK3 (WO 03/082853). Thus, it is expected that this compound is well suitable for prevention and/or treatment of conditions associated with cognitive disorders and predemented states, especially dementia, Alzheimer's Disease (AD), Cognitive Deficit in Schizophrenia (CDS), Mild is Cognitive Impairment (MCI), Age-Associated Memory Impairment (AAMI), Age-Related Cognitive Decline (ARCD) and Cognitive Impairement No Dementia (CIND), diseases associated with neurofibrillar tangle pathologies, Frontotemporal dementia (FTD), Frontotemporal dementia Parkinson's Type (FTDP), progressive supranuclear palsy (PSP), Pick's Disease, Niemann-Pick's Disease, corticobasal degeneration (CBDi), traumatic brain injury (TBI), dementia pugilistica, Down's syndrome, vascular dementia, Parkinson's Disease (PD), postencephelatic parkinsonism, dementia with Lewy bodies, HIV dementia, Huntington's Disease, amyotrophic lateral sclerosis (ALS), motor neuron diseases (MND, Creuztfeld-Jacob's disease, prion diseases, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD) and affective disorders, wherein the affective disorders are Bipolar Disorder including acute mania, bipolar depression, bipolar maintenance, major depressive disorders (MDD) including depression, major depression, mood stabilization, schizoaffective disorders including schizophrenia, dysthymia, Type I diabetes, Type II diabetes, diabetic neuropathy, alopecia, inflammatory diseases, cancer and bone-related disorders including osteoporosis.
WO 03/082853 discloses a process for the preparation of 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]1H-indole-5-carbonitrile as a free base and the hydrochloride salt thereof. In said process 5-cyanooxindole is reacted with a 2-halopyridin-N-oxide derivative in an inert organic solvent such as tetrahydrofuran, dioxane, dimethylformamide or N-methylpyrrolidin-2-one. The presence of a base is advantageous for the coupling. A temperature range of 0-130° C. was disclosed.
The N-oxide could be removed with phosphorus trichloride in a suitable solvent such as methylene chloride, toluene or ethyl acetate to furnish 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]1H-indole-5-carbonitrile. In the disclosed process the 5-cyanooxindole is expensive and is not available as a commercial bulk substance. At the temperature for the coupling, 130° C., the starting 5-cyanooxindole decomposes. The use of N-oxides on large scale is of concern due to their potential explosive properties. Purification to achieve a pharmaceutically acceptable quality material could only be achieved by column chromatography. This purification technique is not the most practical or economical for large-scale manufacture. In addition, upon scale up low yields where obtained.
In summary, there is a need for a more convenient and more economically efficient process for the manufacturing of 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]1H-indole-5-carbonitrile as a free base and pharmaceutically acceptable salts thereof, especially with regard to large-scale production where factors like costs, manufacturing time, robustness and safety are vital for commercial application. The present invention provides for such a process.